A family of structurally and functionally related neurotrophic factors exist which are collectively known as neurotrophins. The family of neurotrophins includes the nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), neurotrophin-5 (NT-5) and neurotrophin-6 (NT-6).
The neurotrophins exhibit similar structural conformations, including three surface β-hairpin loops, a β-strand, an internal reverse turn region, and N- and C-termini. With respect to sequence similarities, the neurotrophins share approximately 50% amino acid identity. The neurotrophins are also functionally similar in that they each exhibit low affinity binding to a receptor known as the “p75 nerve growth factor receptor” or p75NGFR. Each neurotrophin also exhibits binding to a receptor of the tyrosine kinase (trk) family which is of higher affinity than the binding to the p75 receptor. This interaction is believed to be related to neuron survival, but is also involved with neuron differentiation including process formation. The trk receptor-neurotrophin interaction has been found to be more selective than neurotrophin interaction with the p75NGFR receptor. In particular, NGF binds only a trk receptor known as the TrkA receptor, while BDNF, NT-4 and NT-5 exhibit exclusive binding to a TrkB receptor. NT-3 is less selective and, although it binds primarily with a TrkC receptor, it also exhibits some binding to the TrkA and TrkB receptors (Ibanez et al., EMBO J. 1993, 12:2281).
The neurotrophins function primarily to promote survival of certain classes of peripheral and central neurons both during development and following neuronal damage. NGF, in particular, is involved with the development of neurons in the peripheral nervous system and supports neuronal survival, as well as enhancing and maintaining the differentiated state of neurons. However, in some neurological disease states, the neurotrophins may also support inappropriate neurite outgrowth thereby facilitating the progression of a disease condition. For example, neurotrophins promote the undesirable sprouting of hippocampal “mossy fibres”. Such inappropriate sprouting of mossy fibres is a common accompaniment of epilepsy in humans. It is also postulated that the pain experienced by patients suffering from some chronic pain syndromes may be associated with sprouting of sensory pain fibers responsive to NGF in particular into the spinal cord. In other pathological states, such as Alzheimer's disease, aberrant process growth, known as dystrophic neurite formation, is a strong correlate of disease severity.
Thus, although the neurotrophins are essential for the normal development and growth of neurons, they may be detrimental under certain circumstances. In such instances, ligands capable of inhibiting or reducing selected neurotrophin-mediated activities would be desirable therapeutically to treat neurodegenerative diseases and conditions including neuropathic pain and to repair nervous system injury.